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Thursday, August 21, 2014

The Human Microbiome ~ Myth and mystery

In the 1990’s, antioxidants were the big fashion in food and
health. These antioxidants were mainly vitamins (C and E), pre-vitamins
(beta-carotene) and plant constituents of various kinds (e.g. coumarin,
flavonoids, thymol). Studies showed that rates of cancers across many countries
were directly correlated with plasma levels of antioxidants. Laboratory studies
showed that the damaging effect of pro-oxidant metals such as copper could be
reduced with the addition of antioxidants. Every disease imaginable was
included in the antioxidant Klondike. And of course we had the race to the
finish culminating in a trial of Chinese smokers (smoking is pro-oxidant) with
antioxidant supplements which showed the opposite to what was hoped for - cancer
rates were increased! Many other trials were conducted but to date, little
evidence exists to support the theory that taking antioxidant supplements
reduces any disease risk. Of course that doesn’t bother the health food
industry and to some extent the food industry from hyping up the antioxidant
myth.This blogger learned one lesson
from the antioxidant saga namely that any nutritional theory that is putatively
related to many diseases, is a theory about to be shelved.

In today’s world of food and health, that role is played by
the human gut microbiota. The front covers of The Economist, the New York Times
magazine, Nature, Scientific American and others have highlighted articles with
titles such as “Microbes maketh man” or “Our other genome”. There are wow
statistics that journalists love: 100 trillion bacteria in our gut accounting
for 1.5 kg of our bodyweight with 100 times more genes than we have (“We” are
referred to as “Hosts”!). To journalists, it is an astonishing mystery that
bacteria, previously thought to be bad for health were in fact our single most
important protection against an array of diseases. A search of the PubMed database shows the term
“Gut microbiome” is associated with the following diseases (number of published
papers in brackets): obesity (628), cancer (381), diabetes (350), allergy
(260), depression (48) and autism (33). I stopped there but I’m sure I could go
further. The point is that the gut microbiota is the new unifying theory of
life and death.

A very welcome paper in this week’s Nature bears the title
“Microbiome science needs a healthy dose of sceptism”[1].
The author’s first point of criticism is that the techniques used to
characterise the microbiota genome often lack direct links to known functions.
He points out that his team has shown that vaccination eliminated 30% of known
pneumococcal strains in a human population but only because they knew which
genes to focus on. In the case of the human microbiota genome, we might know
that it differs between say normal weight and obese subjects. But that’s all we
know. We cannot tell what part of the microbiota genome is directly linked in a
causal manner to obesity.His second
criticism is linked to this in that cause and effect are misinterpreted when
looking at gut microbiota. He cites a paper, which shows that changes in the
human microbiota correlate with measures of frailty in older persons. So too
did dietary patterns. The conclusion was that poor diet altered the gut
microbiota and thus led to frailty. The opposite was not considered, namely,
that frailty led to poor diets that in turn altered gut microbiome patterns.
His third criticism is that most of the studies lack any mechanistic
explanation based on experimental investigation. In that respect the field is
similar to nutritional epidemiology where correlations dominate and shape
policy in the absence of any experimental proof. So if we consider the
microbiome-diet-frailty issue, a simple test would be to take a cohort of frail
persons and through physiotherapy, counseling and nutritional support reduce
their frailty. If a significant improvement in frailty had no effect on the
microbiome, we can dismiss that theory. Alternatively, frail persons could
receive faecal transplants to modify their microbiota and examine the effect of
improved microbiota on frailty. His fourth criticism relates to the quality of
the data on the microbiota and health vis-à-vis the real world. He highlights
the fact that many of the studies that show the importance of the gut
microbiota are conducted in germ-free mice. Such mice live in an aseptic bubble
that makes them generally ill and with poor food intake. Finally he asks if
there might be a confounding factor such that the real force driving the
disease is one thing and the altered microbiota simply an observer, equally
effected by the true driver.

In his paper, Professor Hanage who works in Harvard, cites a
blog by Professor Jonathan Eisen of the University of California at Davis in
which he makes an award for “Overselling the microbiome”[2].
He shows how research results are manipulated by university press offices and
swallowed easily by journalists. Two collaborating Swedish university research
groups published a paper in Nature Communications[3]
and they wrote thus:

“Our finding of
enriched levels of phytoene dehydrogenase in the metagenomes of healthy
controls and its association with elevated levels of β-carotene in the serum may
indicate that the possible production of this
anti-oxidant by the gut microbiota may have a positive health
benefit”.

“Our results indicate
that long-term exposure to carotenoids, through production by the bacteria in
the digestive system, has important health benefits. These results should make
it possible to develop new probiotics. We think that the bacterial species in
the probiotics would establish themselves as a permanent culture in the gut and
have a long-term effect”. “By examining the patient's bacterial microbiota, we
should also be able to develop risk prognoses for cardiovascular disease",
says Fredrik Bäckhed, Professor of Molecular Medicine at Gothenburg University.
"It should be possible to provide completely new disease-prevention
options".

The present fashion of the microbiota has a powerful
scientific dimension but it is over-hyped and under-studied at the human
experimental level. Whist many good human experiments are done to study the
human microbiota, most are poorly constructed, observational and in rodents,
normal or germ free.

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"Ever seen a fat fox ~ Human obesity explored"

About Me

I graduated from University College Dublin in 1971 with an Masters in Agricultural Chemistry, took a PhD at Sydney University in 1976 and joined the University of Southampton Medical School as a lecturer in human nutrition in 1977. In 1984 I returned to Ireland to take up a post at the Department of Clinical Medicine Trinity College Dublin and was appointed as professor of human nutrition. In 2006 I left Trinity and moved to University College Dublin as Director of the UCD Institute of Food and Health. I am a former President of the Nutrition Society and I've served on several EU and UN committees on nutrition and Health. I have published over 350+ peer reviewed scientific papers in Public Health Nutrition and Molecular Nutrition and am principal investigator on several national and EU projects (www.ucd.ie/jingo; www.food4me.org). My popular books are "Something to chew on ~ challenging controversies in human nutrition" and "Ever seen a fat fox: human obesity explored"